Antibiotic that Works in Low-Oxygen Setting Prevents Reactivation of TB Infection, Says Pitt Team

PITTSBURGH, July 23, 2012 – Reactivation of latent tuberculosis infection could be better prevented if a drug that is effective against bacteria in low-oxygen environments is added to the treatment regimen, according to researchers at the University of Pittsburgh School of Medicine in this week’s online Early Edition of the Proceedings of the National Academy of Sciences.

Pulmonary TB is spread through infected air droplets, said senior author JoAnne L. Flynn, Ph.D., professor, Department of Microbiology and Molecular Genetics, Pitt School of Medicine. People can develop active TB with cough, fever, night sweats and fatigue, but most develop an asymptomatic “latent” infection where the bacteria, called Mycobacterium tuberculosis, can remain in the lung tissue walled off in a lesion called a granuloma. In some, particularly the elderly or immune-compromised, the infection can reactivate years later.

“An estimated 2 billion people worldwide are latently infected with TB, so it’s imperative to have treatment strategies that can prevent the disease from becoming active again,” Dr. Flynn said. “The infection reactivates in about 10 percent of patients with healthy immune systems, and each case of infectious TB can lead to more than seven new cases. ”

Currently, active TB that is not resistant to antibiotics is treated with a so-called “short course” of two months of the drugs isoniazid (INH), rifampin (RIF), pyrazinamide and ethambutol, followed by four more months of INH and RIF. Latent infection is treated with nine months of INH, which acts primarily on replicating bacteria. It’s challenging for patients to continue the treatments to their conclusion, so new drugs that act more quickly would be very helpful, noted Dr. Flynn, who also is an associate member of the University of Pittsburgh’s Center for Vaccine Research.

Previous research has shown that the TB bacilli that can survive low-oxygen conditions are not susceptible to INH. Yet the caseous (“cheese-like”) granulomas commonly seen in human infection have areas of tissue death, or necrosis, associated with a hypoxic environment. That led the team to examine whether metronidazole (MTZ), an antibiotic that is known to be effective against non-replicating bacteria in low-oxygen settings, would be better able to eradicate the TB bacilli contained in the granuloma.

The researchers found that in a macaque model of TB, two months of MTZ alone was as effective as two months of INH and RIF at preventing reactivation of the infection induced by an agent called anti-tumor necrosis factor antibody, which triggered disease in most of the untreated animals. Also, adding MTZ to an INH and RIF regimen reduced bacterial burden in monkeys with active TB within two months.

“Instead of merely active or latent, TB can be considered a spectrum of the same disease related to bacterial burden,” Dr. Flynn said. “The next step is to find better drugs that work in these hypoxic areas of granulomas because MTZ can be difficult to tolerate over an extended time.”

Co-authors of the paper include Philana Ling Lin, M.D., Children’s Hospital of Pittsburgh of UPMC; Veronique Dartois, Ph.D., Novartis Institute for Tropical Diseases, Singapore; Paul J. Johnston, Department of Microbiology and Molecular Genetics, Pitt School of Medicine; Christopher Janssen, D.V.M., and Edwin Klein, D.V.M., Division of Laboratory Animal Research, University of Pittsburgh; and Laura Via, Ph.D., Michael B. Goodwin, and Clifton E. Barry III, Ph.D., all of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

The project was funded by the Bill and Melinda Gates Foundation Grand Challenge 11 “Drugs for Latent TB”; the Otis Foundation; and, in part, by the Intramural Research Program of NIAID.

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